Introduction - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 2

1.1 Purpose

It is well understood and accepted that the aerodynamic particle size distribution
(APSD) of the pharmaceutical aerosol emitted upon actuation of an OIP is a critical
in vitro quality attribute [ 1 ]. This is because the OIP has to produce an aerosol with
appropriate aerodynamic properties to deposit in a reproducible manner the inhaled
medication beyond the upper airway comprising the oropharynx into the airways of
the lungs. Ultimately, the size properties of OIP aerosols that are measured in the
laboratory should be described in ways that are meaningful in the clinical context,
as well as suitable for the purpose of product quality control (QC) during develop-
ment and production. In practice, meeting the former need has proven a diffi cult
task, mainly because apart from that natural variability in breathing behavior associ-
ated with the same patient at different occasions, factors such as patient-to-patient
differences in airway caliber as well as disease modality play an important part in
the eventual clinical outcomes. Furthermore, clinical measures, such as forced expi-
ratory volume in one second ( FEV 1 ), are intrinsically less sensitive to discern small
changes in aerosol particle size distribution, compared with currently available lab-
oratory methods. Given this framework, the purpose of this topic is to present cas-
cade impaction as the most suitable method for the laboratory determination of OIP
aerosol size properties, both in the context of product QC and in the still developing
fi eld of linking these in vitro measures of size to clinical performance of the
product.
The multistage CI, originally developed as an air sampling device for use in
occupational hygiene, has in the past 30-plus years been adopted and adapted by the
community involved with the laboratory measurement of aerosols emitted from
OIPs. This outcome is primarily because the impactor-based size-separation pro-
cess is based on the aerodynamic diameter-related size, rather than on physical (i.e.,
microscopic) size of the airborne particles [ 2 ]. This aerodynamic size scale is more
appropriate to describe the motion and ultimate deposition of aerosol particles in the
airways of the human respiratory tract (HRT) [ 3 , 4 ]. The ability to recover quantita-
tively the drug substance(s), also known as active pharmaceutical ingredient(s)
(APIs), of the aerosolized formulation from the components of the CI is also
regarded as being of crucial importance by regulatory agencies [ 5 ]. This situation
precludes the adoption of more rapid and less labor-intensive techniques that do not
have the API-detection capability (Table 1.1 ).
The development of ways in which the cascade impaction method might be
improved grew out of increasing awareness by stakeholders in the early to mid
2000s that the existing full-resolution CI-based procedures were not only labor
intensive, but prone to a multiplicity of errors arising from the large number of indi-
vidual (and still mostly manual) operations that have to be performed correctly [ 1 ].
The AIM concept was the fi rst of these ideas that, although identifi ed conceptu-
ally in the mid-1990s [ 6 ], did not gain traction until the false but pervasive paradigm
that a multistage impactor somehow is a simulator of the HRT was dispelled by